High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling.
High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling.
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DOI：
10.1038/ncomms9243
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发表时间：
2015-09-10
影响因子：
16.6
通讯作者：
Song K
中科院分区：
文献类型：
--
作者：
Zhao Y;Londono P;Cao Y;Sharpe EJ;Proenza C;O'Rourke R;Jones KL;Jeong MY;Walker LA;Buttrick PM;McKinsey TA;Song K
最近已经证明，通过强制表达心肌生成因子，GMT （GATA4, Mef2C, Tbx5）或GHMT (GATA4, Hand2, Mef2C, Tbx5)，成纤维细胞直接重编程为心肌细胞，这提示了一种新的心脏修复治疗策略。然而，目前的方法效率低下。在这里，我们证明了促纤维化信号可以有效地对抗心脏重编程。值得注意的是，使用靶向转化生长因子-β或rho相关激酶途径的小分子抑制促纤维化信号传导可将胚胎成纤维细胞转化为功能性心肌细胞样细胞，效率高达60%。相反，这些促纤维化信号网络的过度激活会减弱心脏重编程。此外，抑制促纤维化信号显著增强心脏重编程的动力学，在不到2周的时间内出现自发收缩的心肌细胞，而单独使用GHMT则需要4周。这些发现为成纤维细胞心脏转化的分子机制提供了新的见解，并将加强为临床应用产生心肌细胞的努力。将心脏成纤维细胞直接重编程为心肌细胞是一种有吸引力的心脏再生策略，但该过程的低效率阻碍了它的发展。本文作者表明，当促纤维化信号被抑制时，小鼠成纤维细胞可以高效地重编程为功能性心肌细胞。
Direct reprogramming of fibroblasts into cardiomyocytes by forced expression of cardiomyogenic factors, GMT (GATA4, Mef2C, Tbx5) or GHMT (GATA4, Hand2, Mef2C, Tbx5), has recently been demonstrated, suggesting a novel therapeutic strategy for cardiac repair. However, current approaches are inefficient. Here we demonstrate that pro-fibrotic signalling potently antagonizes cardiac reprogramming. Remarkably, inhibition of pro-fibrotic signalling using small molecules that target the transforming growth factor-β or Rho-associated kinase pathways converts embryonic fibroblasts into functional cardiomyocyte-like cells, with the efficiency up to 60%. Conversely, overactivation of these pro-fibrotic signalling networks attenuates cardiac reprogramming. Furthermore, inhibition of pro-fibrotic signalling dramatically enhances the kinetics of cardiac reprogramming, with spontaneously contracting cardiomyocytes emerging in less than 2 weeks, as opposed to 4 weeks with GHMT alone. These findings provide new insights into the molecular mechanisms underlying cardiac conversion of fibroblasts and would enhance efforts to generate cardiomyocytes for clinical applications. Direct reprogramming of cardiac fibroblasts into cardiomyocytes is an attractive strategy for heart regeneration, but it is hampered by the low efficiency of the process. Here the authors show that mouse fibroblasts can be reprogrammed with high efficiency into functional cardiomyocytes when pro-fibrotic signaling is inhibited.